Background

Radiation therapy is a mainstay in the treatment of both primary and recurrent gastrointestinal (GI) and pelvic malignancies.
[1, 2] Combining treatment modalities (surgery, chemotherapy, radiation) allows for the best possible outcome in patients with these malignancies. One of the major and debilitating adverse effects of radiation therapy is the development of radiation enteritis and proctitis. Both radiation enteritis and proctitis have acute (early) and chronic (late) manifestations.

The direct effects of radiation on the bowel mucosa lead to acute radiation enteritis. Acute radiation enteritis is exceedingly common; virtually every patient has some manifestation of acute radiation-induced injury of the GI tract in the form of abdominal cramping, tenesmus, urgency, bleeding, diarrhea, and incontinence. Typically, these patients are managed symptomatically and supportively. The symptoms of most patients resolve within weeks of radiation therapy cessation.

Chronic radiation enteritis is an indolent but relentlessly progressive disease. Patients may present with symptoms within months or even decades after the injuring radiation therapy. Chronic intestinal radiation injury is a result of transmural bowel damage with associated obliterative endarteritis.

Treatment of these patients is extremely challenging. Initial nonoperative modalities include diet modification, nutritional support, and control of symptoms with medications.
[3] Severe, progressive disease may require surgical intervention, especially for complications, such as fistula formation, obstruction, perforation, and hemorrhage.

Although the benefits of treatment with radiation are well established, damage to the healthy, nonneoplastic tissue may be severe.
[4] The rectum is more commonly injured because of its fixed position in the pelvis. Postoperative adhesions that fix small bowel loops within the pelvis make these loops susceptible to radiation injury. Because radiation is increasingly used to treat pelvic malignancies, the surgical prevention and treatment of the complications of radiation enteritis and proctitis continues to evolve.

Just 2 years after the discovery of x-rays in 1895, Walsh reported the first case of radiation-induced enteritis.
[5] A patient who worked with x-rays had developed abdominal pain and diarrhea, symptoms that resolved with the use of a lead shield. In 1917, the first case was reported of the development of radiation enteritis following the use of radiotherapy to treat malignancy. In 1930, researchers reported the development of factitial proctitis in a group of patients who received pelvic radiation to treat malignant disease.

As the use of radiation therapy and x-rays in medicine increased, the harmful adverse effects were better recognized. Warren and Friedman described both the early and late effects of radiation therapy on the intestine.
[6] Once the risks associated with radiation therapy were recognized, attempts followed to prevent these complications. The development of improved dosimetry techniques, as well as patient selection and positioning during delivery of radiation therapy, were crucial to decrease the harmful effects of radiation on the intestines.

The history of surgical prevention of small-bowel radiation injury is based on the principle of abdominopelvic partitioning. The goal of this procedure is to keep the highly radiation-sensitive small intestine out of the pelvis. In 1979, Freund et al published the first report of a surgical procedure to create abdominopelvic partitioning.
[7] In 1984, Russ et al described the use of an omental pedicle flap. In 1985, DeLuca and Ragins described the creation of an omental envelope to enclose the small bowel.
[8]

In 1992, Lechner and Cesnik again described this technique and coined the term abdominopelvic omentopexy.
[9] In 1995, Choi and Lee described the omental hammock technique.
[10] The omental pedicle, based on the left gastroepiploic artery, is sutured circumferentially to the parietal peritoneum at the level of the sacral promontory and the umbilicus. A hammock is created within which the small bowel rests; the hammock prevents the bowel from entering the pelvic cavity.

Patients often lack adequate amounts of omentum or peritoneum to create an abdominopelvic separation. In 1979, Lavery et al reported their use of gauze packs encased in a latex dam to protect the abdominal viscera during high-dose radiotherapy for osteogenic sarcoma of the iliac bone.
[11] In 1983, Sugarbaker described the use of a silicone breast implant to occupy the pelvic cavity.
[12] Hoffman reported the use of saline-filled tissue expanders to occupy the pelvic cavity. In 1984, Devereux et al described, in a group of 60 patients, the use of mesh slings after resection of rectal or gynecologic malignancies.
[13]

Historically, the surgical procedures to treat the complications of radiation enteritis have been as minimally invasive as possible, with the goal of relieving symptoms. Patients with fistulas and obstruction underwent bypass, and patients with bleeding associated with radiation proctitis underwent diverting colostomy. In 1976, Swan et al reported that resection for fistulas and obstruction was associated with prohibitive rates of morbidity and mortality. In 1984, Webbes et al and Goligher et al reaffirmed these recommendations. Multiple reports suggest that resection reduces the reoperative rate and improves the 5-year survival rate but leads to a higher rate of postoperative mortality.

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Pathophysiology

Histopathologic findings in acute radiation-related intestinal damage include the following characteristics:

Transient mucosal atrophy

Submucosal edema

Inflammation and infiltration of the lamina propria with polymorphonuclear leukocytes and plasma cells

In addition, mitotic arrest, karyorrhexis, and lysis of the crypt and deep epithelial cells are observed. If the submucosal damage is not prominent, the epithelial cells regenerate and the changes regress. Conversely, severe submucosal changes lead to progression of mucosal injury, ulcerations, and erosion of the villi. The histologic findings in the acute phase correlate poorly with clinical symptoms, but amounts of malabsorption vary because of the mucosal damage.

Repopulation of the mucosal cells occurs in the later stage of the acute phase. The severity of the damage to supportive connective tissue limits the degree of reepithelialization. The fibrosis of the underlying connective tissue causes patchy ischemia of the mucosa, which may cause ulceration. Local trauma or infection often precipitates these ulcers.

Histologically, obliterative endarteritis of the small vessels in the intestinal wall characterizes chronic radiation intestinal injury. Associated lymphoid atrophy, lymphatic dilation, and fibrosis of the submucosal tissue are observed. The progressive vascular sclerosis leads to chronic ischemia of the overlying tissue, ultimately resulting in mucosal atrophy. Scar tissue replaces the submucosal tissue, resulting in further decrease in vascularity and contracture of the intestinal wall. Chronic mucosal ulceration may result in fistula formation and hemorrhage.

In the later stages, the colon and rectum are susceptible to the development of radiation-induced carcinomas, which may manifest as ulcers or masses and are often adenocarcinomas.

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Etiology

Radiation injury to the small and large bowel is due to damage to the lipid layer of the cell membrane, proteins, and cellular DNA. The effects are most marked in tissues containing cells with a high mitotic rate.

Patient-related factors and the method of radiation therapy administration may intensify the effects of radiation-induced intestinal injury. Patient-related risk factors that are associated with an increased risk of radiation-induced enteropathy include the following:

Advanced patient age

Prior abdominal surgery leading to intraperitoneal adhesions - Adhesions fix portions of the small or large intestine in the radiated field

Analysis of multiple risk factors for predictive value demonstrated that multiple laparotomies, hypertension, and thin physique had the highest correlation with the development of radiation enteritis.

Administration of chemotherapy with radiation therapy correlates with an increased incidence of radiation-related intestinal damage. Several studies have documented this effect as well as the recall phenomenon, in which radiation followed with chemotherapy leads to a recurrence of the symptoms of radiation-induced intestinal injury.

The degree of intestinal injury is directly related to the total radiation dose, the fractionation, and the distribution of the dose in tissues peripheral to the target area. Early in the evolution of radiation therapy, large single radiation doses were noted to cause severe or even lethal adverse effects; the same cumulative dose given as small fractions over the course of several days or weeks was better tolerated.

For example, a single 30-Gy dose of radiation to the esophagus is tolerated poorly; however, when the dose is fractionated and spread over 4-6 weeks, even a total dose of 60-70 Gy is tolerated. Similarly, Deore et al demonstrated an increased incidence (8.2-33.3%) of late rectal and rectosigmoid complications as the dose per fraction increased from 2 Gy to 5.4 Gy in patients treated for cancer of the cervix with radiation alone.
[14]

Excessive exposure of adjacent normal tissue to radiation also contributes to the development of radiation-induced enteropathy. Current techniques allow for a focused delivery of radiation energy to the target tissues with intracavitary radiation as well as external beam with supervoltage radiation, multiple portals, and the improved shielding of adjacent normal structures. Radiotherapy’s adverse effects may be decreased with a combination of the following:

Multidirectional, sharply collimated beams

Computer-assisted dosimetry

More stable intracavitary applicators

Extended intervals between fractionated doses and a lower dose per fraction

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Epidemiology

More than 200,000 new cases of prostate, cervical, rectal, testicular, bladder, and endometrial cancer are diagnosed each year. Approximately 50% of these patients require radiation therapy.

Acute radiation-induced injury to the GI mucosa occurs in virtually all patients undergoing radiation therapy. In more than 80% of patients, treatment can control the symptoms of tenesmus, diarrhea, and hematochezia. The use of antispasmodics, analgesics, and antidiarrheal agents combined with intravenous fluid replacement are often adequate to treat patients with acute radiation enteritis and proctitis.

In a small number of patients, the severity of symptoms requires cessation of radiation therapy. This occurs most commonly in patients who are receiving concomitant chemotherapy or in those at high risk to develop radiation enteritis prior to initiation of therapy.

Approximately 5-15% of patients who receive abdominal or pelvic radiotherapy develop pronounced chronic radiation enteritis. Up to 50% of patients with severe chronic radiation enteropathy require surgical intervention. In patients who receive postoperative radiotherapy, as many as 30-40% experience chronic diarrhea. More than 1 million patients in the United States may have bowel dysfunction related to radiotherapy.

Abayomi et al investigated the incidence of chronic radiation enteritis in 117 women who had undergone radiotherapy for cervical or endometrial cancer. They also sought to determine whether radiation level or cancer stage was associated with an increased risk for enteritis. In response to a questionnaire relating to bowel problems and quality of life, 47% of patients had scores indicating the presence of chronic radiation enteritis. Although scores did not significantly correlate with radiation dose or cancer stage, the investigators determined that scores indicative of chronic radiation enteritis were most prevalent among younger women and among patients who had been treated for cervical cancer.
[15]

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Prognosis

Surgical procedures on radiated intestine carry a morbidity of 12-65% and a mortality of 2-13%. The wide range reflects the diverse surgical procedures used to treat complications of radiation.

Preoperative radiotherapy has been attributed with a reduced cancer-specific mortality compared with postoperative radiotherapy in soft-tissue sarcoma. Additional studies with larger patient numbers are needed.
[16]

Factors that adversely affect prognosis after surgery include intestinal leak, surgery for fistula or perforation, and progression of radiation-induced damage after the initial operation.

An anastomotic breakdown incidence as high as 50% has been noted after resection and anastomosis involving diseased segments of bowel in radiation enteritis.

Almost 50% of patients who survive a laparotomy for radiation bowel injury require further surgery for ongoing bowel damage from radiation. A mortality as high as 25% is reported for patients who require a second surgical procedure. The mortality is directly attributable to the radiation enteritis and complications of treatment.

In an analysis of 77 patients diagnosed with radiation enteritis or proctitis, Ruiz-Tovar et al compiled various statistics relating to the location, treatment, and outcome of these injuries.
[17] Radiation injury sites were as follows:

DeLuca FR, Ragins H. Construction of an omental envelope as a method of excluding the small intestine from the field of postoperative irradiation to the pelvis. Surg Gynecol Obstet. Apr/1985. 160(4):365-6. [Medline].

Omental transposition flap based on left gastroepiploic vascular bundle is sutured in place along the left paracolic gutter, and the omental bulk is packed into the pelvic cavity.

Omental envelope is created by draping the omentum over the small bowel and suturing the lateral edges to the peritoneum in the paracolic gutters. The lower edge is sutured to the posterior abdominal wall at the level of the sacral promontory.

An omental pedicle based on the left gastroepiploic vessels is sutured circumferentially to the parietal peritoneum at the level of the sacral promontory and umbilicus. This creates a sling, or hammock, which contains the bowel and prevents it from entering the pelvis.

An absorbable mesh sling is created by suturing a Vicryl or Dexon mesh to the sacral promontory, lateral abdominal wall, and anterior abdominal wall at the level of the umbilicus. Within this mesh sling, the small bowel loops are contained and held out of the pelvic cavity.

Marc D Basson, MD, PhD, MBA, FACS Senior Associate Dean for Medicine and Research, Professor of Surgery, Pathology, and Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences